Magnetic nanoparticles have been widely used in such areas of the biomedical field as cell labeling, magnetic resonance imaging (MRI), drug delivery, and hyperthermia. Among a variety of kinds of magnetic nanoparticles, superparamagnetic iron oxide based nanoparticles have been broadly studied as a T2 MRI contrast agent because they have high magnetic susceptibility and superparamagnetic properties. T2 MRI contrast agents which are presently commercially available, such as Feridex, Resovist, and Combidex, are manufactured using reduction of iron chloride and co-precipitation in a hydrophilic polymer aqueous solution (C. W. Jung, et. al. Magn. Reson. Imaging 1995, 13, 661).
However, iron oxide nanoparticles thus manufactured have some defects. Because they are synthesized in an aqueous solution, it is difficult to perform a high-temperature reaction of 100° C. or more, and magnetism is lowered due to low crystallinity. Recently, to overcome such defects as these, thorough research is ongoing into how to improve the magnetism of materials and develop new T2 MRI contrast agents. Methods of synthesizing iron oxide nanoparticles having uniformity and high crystallinity were developed over the past ten years and mass production thereof has become possible (J. Park, et. al. Nat. Mater. 2004, 3, 891). For example, it is reported that manganese ferrite (MnFe2O4) nanoparticles have very high magnetism and thus exhibit superior T2 contrast effects (J.-H. Lee, et al. Nat. Med. 2007, 13, 95).
Unlike commercially available T2 MRI contrast agents, however, magnetic nanoparticles synthesized at a high temperature of 100° C. or more are not dispersed in an aqueous solution because they are coated with a hydrophobic surfactant. For biomedical applications, such hydrophobic magnetic nanoparticles should be coated with a biocompatible and hydrophilic material such as dextran, starch, polyethyleneglycol (PEG) or silica. Currently, dextran-coated iron oxide nanoparticles are medically approved as a T2 MRI contrast agent and are being used. However, because hydrophilic dextran is dispersed only in an aqueous solution, it is difficult to directly coat hydrophobic surfactant-coated nanoparticles. Thus, many attempts have been made to carry out additional modification so that hydrophilic dextran is dispersed in an organic solvent, or to disperse the nanoparticles in an aqueous solution before coating with dextran, but such methods are complicated and the yield is low.
In order to modify the structure of the material or improve the properties to solve the aforementioned problems, annealing treatment has been utilized. However, in the case of nanoparticles, high-temperature annealing treatment causes the particles to agglomerate thus losing the inherent properties of nanoparticles. To prevent such side-effects, recently a wrap-bake-peel method has been devised (Y. Piao, et al. Nat. Mater. 2008, 7, 242), so that the nanoparticles are coated with silica to prevent the nanoparticles from agglomerating during the annealing treatment.
Another method of preventing the particles from agglomerating during the annealing treatment, in which salt particles are used, has been proposed. Platinum-iron (Pt—Fe) nanoparticles having a face centered tetragonal (FCT) structure are mixed with an excess of sodium chloride (NaCl) followed by carrying out high-temperature annealing treatment thus forming Pt—Fe nanoparticles having a face centered cubic (FCC) structure (D. Li, et al. J. Appl. Phys. 2006, 99, 08E911). High-temperature annealing treatment modifies the crystalline structure of particles and thereby magnetism is enhanced.
In recent methods, NaCl is removed after which nanoparticles are dispersed in an aqueous solution and then coated with cysteine thus obtaining a very stable aqueous solution of nanoparticles (A. Delattre, et al. Small 2010, 6, 932).